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Stable liquid interferon formulations

a liquid formulation and interferon technology, applied in the direction of drug compositions, peptide/protein ingredients, immunological disorders, etc., can solve the problems of lack of interferon stability in solutions and other products, especially in purified form, and limited utility of proteins

Inactive Publication Date: 2008-02-28
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a stable liquid formulation of interferon-beta that does not require prior lyophilization and has improved stability compared to lyophilized formulations. The liquid formulation includes an interferon-beta stabilizing agent, such as an amino acid or salt, and a buffer to maintain the pH. The liquid formulation has advantages such as smaller injection volume, improved dosing accuracy, and improved safety due to simplified packaging and reduced chance of needle punctures. The invention also provides a kit for parenteral administration and a process for stabilizing interferon-beta in liquid pharmaceutical compositions. The liquid formulation can be stored for a long period of time and is easily made and administered.

Problems solved by technology

It is known, however, that proteins in their purified form are especially susceptible to degradation.
The lack of interferon stability in solutions and other products has heretofore limited its utility.
Lyophilized preparations have the disadvantage of requiring complex packaging since a separate supply of sterile water for injection is required.
Moreover, lyophilized preparations require several manipulations prior to use, thus increasing the possibility of needle sticks and dropped components during preparation for injection.
These manipulations are especially problematic for patient populations that exhibit muscle weakness and poor coordination, such as people with multiple sclerosis (MS).

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Assay Methods

[0079] Several well-characterized methods are used to determine the physico-chemical properties of the interferon-beta in our liquid formulations and these methods may be used to monitor properties of other interferons as well.

[0080] The presence / absence of insoluble aggregate is monitored by measuring the absorbance at 320 nm and transmittance at 580 nm. The concentration of soluble protein is determined by either measurement of absorbance at 278-280 nm (with an extinction coefficient of 1.5) or by reverse-phase high performance liquid chromatography (HPLC) using known concentrations of interferon-beta spiked in the formulation buffer as standards. The liquid formulation samples are centrifuged prior to assay. The soluble aggregate percentage is determined by separating aggregates from interferon-beta monomer by size exclusion chromatography on a TSK-Gel® G2000SWXL column (Toso Haas, Montgomeryville, Pa.). The peak areas monitored at 280 nm are used to calculated the...

example 2

Choice of Buffer System

[0086] We prepared three sets of buffers containing between nine and 10 different components for each set. Set I contains a series of sodium phosphate and / or 100 mM sodium chloride solutions between pH 4.0 and 7.2. Set II contains an additional series of sodium citrate buffers between pH 4.0 and 7.0. Set III contains a series of sodium succinate, sodium acetate and sodium carbonate buffer solutions, all combined with 100 mM sodium chloride, having pH values ranging from 4.0 to 7.2. Two other solutions replaced the sodium chloride with 50 mM sodium sulfate at a pH of 4.0 and 7.2.

[0087] Thawed, bulk interferon-beta is dialyzed into different buffers overnight at 2-8 degrees C. with at least two buffer exchanges, then sterile filtered prior to use. Protein concentrations are determined by absorbance at 278 nm (with extinction coefficient of 1.5 mg−1 ml.cm−1) and all samples contained 140 ug / ml or 150 ug / ml interferon-beta. Samples are filtered and split into fo...

example 3

The Effect of Cavitation

[0089] During our pH screening experiments described in Example 2, we discovered that the head space of the storage tubes appears to be critical for loss of protein of some of the samples. With 1.5 ml of the samples in 2.2 ml volume tubes, no loss of protein was observed. On the contrary, 1.2 ml of sample produced significant increase in aggregates. This is consistent with our observations that formation of aggregated interferon-beta during the viral inactivation step of the purification process is dependent on the level of dissolved oxygen during this step.

[0090] In brief, the viral inactivation step involves adjusting the pH of the chelating Sepharose eluate (see Section C) from 7.85±0.25 to between 2.5 to 3.5 with 15% phosphoric acid, holding the acidified eluate for 120-135 minutes, and then readjusting the pH to 6.7±0.7 with 0.5 N sodium hydroxide. All steps are performed at 2-8 degrees C. We designed a study to determine if a relationship exists betwe...

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Abstract

Liquid interferon compositions having a pH between 4.0 and 7.2 are described. The compositions comprise interferon-beta and a stabilizing agent at between about 0.3% and 5% by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine. If needed, salt is added to provide sufficient ionic strength. The liquid composition has not been previously lyophilized or previously cavitated. The liquid is preferably contained within a vessel having at least one surface in contact with the liquid that is coated with a material inert to adsorption of interferon-beta. A kit for parenteral administration of a liquid interferon formulation and a method for stabilizing liquid interferon compositions are also described.

Description

FIELD OF THE INVENTION [0001] This invention relates to methods for stabilizing human interferon-beta and to stable, interferon-beta liquid formulations. BACKGROUND OF THE INVENTION [0002] Interferons are proteins having a variety of biological activities, some of which are antiviral, immunomodulating and antiproliferative. They are relatively small, species-specific, single chain polypeptides, produced by mammalian cells in response to exposure to a variety of inducers such as viruses, polypeptides, mitogens and the like. Interferons protect animal tissues and cells against viral attack and are an important host defense mechanism. In most cases, interferons provide better protection to tissues and cells of the kind from which they have been produced than to other types of tissues and cells, indicating that human-derived interferon should be more efficacious in treating human diseases than interferons from other species. [0003] There are several distinct types of human interferons, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/21A61K47/18
CPCA61K9/0019A61K47/183A61K38/215A61K38/21A61P37/00A61K47/10C07K14/565
Inventor DIBIASE, MARY D.CHUNG, WEN-LISTAPLES, MARKSCHARIN, ERIC
Owner BIOGEN MA INC
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